Antibody-drug conjugates which are useful for the treatment of cancer and other diseases are commonly composed of three distinct elements: a cell-binding agent; a linker; and a cytotoxic agent. One of the commonly used manufacturing processes comprises a modification step, in which the cell-binding agent is reacted with a bifunctional linker to form a cell-binding agent covalently attached to a linker having a reactive group, a purification step in which the modified antibody is purified from the other components of the modification reaction, a conjugation step, in which the modified cell-binding agent is reacted with a cytotoxic agent to form a covalent chemical bond from the linker (using the reactive group) to the cytotoxic agent, and a second purification step, in which the conjugate is purified from the other components of the conjugation reaction.
Recent clinical trials have shown a promising role for antibody-drug conjugates in the treatment of many different types of cancers. Therefore, there is a need to produce conjugates of high purity and high stability that can be used to treat patients. Despite advances in preparing antibody-drug conjugates, current processes are limited by several factors. For example, the conjugates produced by these processes comprise an increased amount of impurities, including free cytotoxic agent (e.g., cytotoxic agent dimer related species) and/or high molecular weight species (e.g., dimers and other higher order aggregates). Current purification methods employed in the art, such as tangential flow filtration and adsorptive chromatography, do not efficiently remove these impurities without significantly decreasing the yield and/or are cumbersome for large scale manufacturing processes.
Thus, there remains a need for improved processes of preparing antibody-drug conjugates that are more stable and are of higher purity than antibody-drug conjugates produced by current processes. The invention provides such a process. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.